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The target of rapamycin, the TOR pathway, is essential for vitellogenesis. However, its influence on pathogen transmission remains to be elucidated. Here, we show that rapamycin, an inhibitor of the TOR pathway, effectively suppresses <jats:italic>Plasmodium berghei<\/jats:italic> infection in <jats:italic>Anopheles stephensi<\/jats:italic>. <jats:italic>An<\/jats:italic>. <jats:italic>stephensi<\/jats:italic> injected with rapamycin or feeding on rapamycin-treated mice showed increased resistance to <jats:italic>P<\/jats:italic>. <jats:italic>berghei<\/jats:italic> infection. Exposing <jats:italic>An<\/jats:italic>. <jats:italic>stephensi<\/jats:italic> to a rapamycin-coated surface not only decreased the numbers of both oocysts and sporozoites but also impaired mosquito survival and fecundity. Transcriptome analysis revealed that the inhibitory effect of rapamycin on parasite infection was through the enhanced activation of immune responses, especially the NF-\u03baB transcription factor REL2, a regulator of the immune pathway and complement system. Knockdown of <jats:italic>REL2<\/jats:italic> in rapamycin-treated mosquitoes abrogated the induction of the complement-like proteins <jats:italic>TEP1<\/jats:italic> and <jats:italic>SPCLIP1<\/jats:italic> and abolished rapamycin-mediated refractoriness to <jats:italic>Plasmodium<\/jats:italic> infection. Together, these findings demonstrate a key role of the TOR pathway in regulating mosquito immune responses, thereby influencing vector competence.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009353","type":"journal-article","created":{"date-parts":[[2021,2,24]],"date-time":"2021-02-24T18:45:02Z","timestamp":1614192302000},"page":"e1009353","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":24,"title":["Rapamycin inhibits pathogen transmission in mosquitoes by promoting immune activation"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6723-5312","authenticated-orcid":true,"given":"Yuebiao","family":"Feng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1820-3220","authenticated-orcid":true,"given":"Han","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiumei","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gong","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6794-2604","authenticated-orcid":true,"given":"Jingwen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,2,24]]},"reference":[{"key":"ppat.1009353.ref001","unstructured":"CLEMENTS AN. 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